The tyramine binding site in the central nervous system: An overview

The ³H]Tyramine (TY) binding site is proposed as a high affinity marker of the membrane carrier for dopamine (DA) in synaptic vesicles from DA-rich brain regions. Under precise assay conditions, there is neither a consistent association of TY with the neuronal, cocaine-sensitive DA transporter, nor with mitochondrial or microsomal targets. TY-labeled sites have a high affinity for selected toxins such as the Parkinsonian agent MPP⁺ (1-methyl-4-phenylpyridinium ion), or drugs such as diphenylalkylamine Ca²⁺-channel antagonists. The MPP⁺/TY site interaction, which in the striatum leads to depletion of vesicular DA, occurs in dopaminergic as well as in noradrenergic regions, though with different kinetic profiles. TY-labeled carriers for DA and noradrenaline (NA) in respective vesicles seem to be different entities, which might result in a region-specific rate of toxin sequestration and/or release from heterogeneous vesicles. Whereas MPP⁺ is a potent competitive-type inhibitor of ³H]TY binding, prenylamine-like Ca²⁺-channel antagonists can compete with TY for the vesicle site, in a tetrabenazine- or reserpine-like manner, and also inhibit TY binding thanks to the extra-channel directed impairment of membrane bioenergetics they are proposed to provoke. This follows from the generally-accepted assumption that similar mechanisms are operational for secretory organelles in adrenals and CNS, and from the marked sensitivity of TY binding to miscellaneous energy-disrupting agents. A model is therefore proposed, depicting the TY-, DA- or MPP⁺-labeled, vesicle carrier, as a dimeric protein which may switch from the cytoplasm-oriented, recognition state, to the vesicle-oriented, transport state, thanks to the establishment of an H⁺-ATPase-supported, membrane protein electrochemical gradient.